Copper-catalyzed asymmetric C(sp2)–H arylation for the synthesis of P- and axially chiral phosphorus compounds

Transition metal-catalyzed C–H bond functionalization is an important method in organic synthesis, but the development of methods that are lower cost and have a less environmental impact is desirable. Here, a Cu-catalyzed asymmetric C(sp2)–H arylation is reported. With diaryliodonium salts as arylating reagents, a range of ortho-arylated P-chiral phosphonic diamides were obtained in moderate to excellent yields with high enantioselectivities (up to 92% ee). Meanwhile, enantioselective C-3 arylation of diarylphosphine oxide indoles was also realized under similar conditions to construct axial chirality.

Transition metal-catalyzed C-H bond functionalization is an important method in organic synthesis, but the development of methods that are lower cost and have a less environmental impact is desirable. Here, a Cu-catalyzed asymmetric C(sp 2 )-H arylation is reported. With diaryliodonium salts as arylating reagents, a range of ortho-arylated P-chiral phosphonic diamides were obtained in moderate to excellent yields with high enantioselectivities (up to 92% ee). Meanwhile, enantioselective C-3 arylation of diarylphosphine oxide indoles was also realized under similar conditions to construct axial chirality.
Transition metal-catalyzed C-H bond functionalization has become an important methodology for organic synthesis in terms of atom economy and step economy [1][2][3][4] . Over the past several decades, elegant and efficient palladium-, rhodium-, iridium-, and ruthenium-catalyzed transformations for the stereoselective construction of C-C and/or C-X bonds through C-H activation have been well exploited [5][6][7][8] . In these well-established methodologies, two general strategies have been followed to achieve enantiocontrol: (1) enantio-determining activation of enantiotopic C-H bonds by chiral transition metal complexes; (2) unbiased C-H bond scission followed by stereochemistrygenerating incorporation of coupling partners. To realize those transformations, many chiral ligands and catalysts have been developed to achieve excellent selectivity [9][10][11][12][13] . On the other hand, a costeffective and environmentally benign method to selectively activate inert C-H bonds is still desirable in this field.
In 2008, Gaunt found that diaryliodonium salts could serve as arylating reagents in the copper-catalyzed C-H arylation of indoles, and an acetyl moiety on the N atom switched the regioselectivity from C3 to C2 47 . The author proposed that a highly electrophilic aryl-Cu(III) intermediate was essential to the reactivity. Several groups extended this methodology, and diaryliodonium salts were proven to be powerful arylating reagents for the C-H bond functionalization of arenes [48][49][50][51][52][53][54][55] . While chiral bisoxazolines (BOXs) are common ligands in copper-catalyzed transformations 56-58 , we questioned whether asymmetric Cu-catalyzed C-H bond arylation could be achieved by the combination of chiral bisoxazolines and diaryliodonium salts.

Optimization of reaction conditions
We commenced our investigations with symmetric phosphonic diamide a1 and [PhIMes]SbF 6 with CuI as the catalyst (Table 1; see the SuppIementary Information for more details). Initially, various bisoxazoline ligands were screened, and commercially available chiral BOX L1 generated desired ortho-arylated product b1 in 50% yield with weak enantiocontrol (10% ee, Entry 1). Next, phenyl-substituted spiro-BOXs L2-L5 were examined (Entries 2-5). Cyclopropane-and cyclobutane-backboned ligands L2 and L3 yielded similar results, with moderate ee values, while cyclopentane-backboned spiro-BOX L4 showed low reactivity. The enantioselectivity increased to 75% when the ring size was increased to a cyclohexane structure (Entry 5). A dramatic increase in enantioselectivity from 75 to 90% was observed when 2,3-dihydro-1H-phenalene-backboned BOX L6 was used, which may be attributed to the additional rigidity of the backbone compared to that of L5 (Entry 6). Unfortunately, modifications of the phenyl substituent of L6 did not result in positive effects on selectivity (Entries 7-9). In addition, ligand L10 with a seven-membered ring backbone was also tested and exhibited inferior enantioselectivity (69% ee, Entry 10). Under the same conditions, CuCl resulted in slightly better enantioselectivity than CuI (91%, Entry 11). 2,6-Di-tertbutylpyridine (DTBP) is a general acid side-product scavenger in Gaunt's works with diaryliodonium salts; 47,51 hence, it was also applied in this reaction to improve the yield, but to our surprise, the reaction was severely suppressed (Entry 12). We hypothesized that DTBP might abstract an anion, which facilitates H atom dissociation during C-H bond activation, from the system, so NaOTf as an external anion source was added (Entries 13-15). After investigating the molar ratio of NaOTf, 0.5 mol% was determined to be the best value, affording the product in 97% yield and 91% ee (Entry 14). Thus, we established an optimal catalyst system: CuCl (10 mol%)/L6 (15 mol%) with 1.5 equiv. of DTBP and 0.5 mol% NaOTf in dichloromethane.

Substrate scope
With the optimal conditions in hand, we examined the substrate scope of this enantioselective ortho-C(sp 2 )-H arylation reaction (Fig. 2). Initially, unsubstituted P-tert-butyl-N,N'-diphenyl phosphonic diamine was subjected to the standard conditions, but only trace product was generated, and a bromo moiety ortho to the methyl group in a1   completely inhibited the reactivity (see the SuppIementary Information for details). These findings suggest that the reaction might be controlled by electronics, necessitating electron-donating groups (EDGs) on the substrate. Several phosphonic diamides with different EDGs were tested. Tert-butyl and dimethyl groups exhibited similar inferior enantioselectivities (85%, b2 and b3). A methoxy group at the meta-position reduced the ee value to 86% because of electronic effects (b4), while halogenation could alleviate the impact and lead to improved results (b5, b6). Substrate a7, with a strong electrondonating 3,4-methylenedioxy group, yielded much poorer results, which might be attributed to a faster background reaction. Replacing the butyl moiety on the P atom with a phenyl moiety resulted in only moderate enantioselectivity, which could be explained by the similar steric hindrance between phenyl and arylamine. Next, a series of diaryliodonium salts were synthesized and tested in this reaction (Fig. 3). Halogenation at the para and meta positions of diaryliodonium salts has a negligible influence on the results, except para-fluorination resulted in slightly lower enantioselectivity due to the electron-withdrawing effect (b9-b14). Ortho-fluoro diaryliodonium salt produced the corresponding ortho-arylated product in moderate yield because of steric repulsion but did not affect the selectivity (b15). Other functional groups, such as methyl, trifluoromethyl, ethoxycarbonyl, methoxy, trifluoromethoxy, and tert-butyl groups, exert notable electronic effects on enantioselectivity. Strong electrondonating and electron-withdrawing abilities were both detrimental to stereo-induction, but substituents in the para-position had a more remarkable negative impact than those in the meta-position (b16-b26). The absolute configuration of product b was assigned to be R according to the X-ray crystal diffraction analysis (XRD) of product b18 59 . Finally, heterocyclic diaryliodonium salts were also used in this reaction, and thiophenyl groups were successfully introduced at the ortho-position of a1 with moderate yields and enantioselectivities (b27-b28).
Axially chiral biaryl monophosphines are an important class of ligands in asymmetric catalysis, and the development of the new synthetic protocol for these compounds has attracted much attention 60 . As phosphine oxides are common precursors of trivalent phosphines, we envisioned the developed phosphine oxide-directed  C-H arylation reaction could be extended to the construction of axially chiral biaryl monophosphine oxides 61 . We chose diphenylphosphine oxide indole c1 as the standard substrate under similar reaction conditions (Fig. 4, see SuppIementary Information for detailed condition optimization), and the C-3 phenylated product was obtained in 64% yield with 87% ee. XRD results of d1 indicate the configuration to be R around the axis 62 .
The scope of diphenylphosphine oxide indoles was also investigated, and the isopropyl on the N atom of the indole ring gave similar results to methyl (d2), while results varied with sites of methyl on the indole ring. 5-and 7-methylated substrates produced approximate results (d3 and d5), but methyl on the 6-position generates much poorer stereoselectivity (69% ee, d4). Such results could be explained as follows: EDGs para to C-3 increased the electron cloud density at the reaction site and accelerated the background reaction. Substrate c8 with stronger EDG methoxy on the 5-position also validated this deduction (d9). Conversely, electron-withdrawing groups (EWGs) like chloro and fluoro on the indole ring severely hampered the reaction rate with slight erosion on ee values of products (d6-d8). Next, different functional groups on diphenylphosphine oxide were also screened. Generally, EDGs on phenyl rings benefit the stereocontrol, giving product in 83-90% ee with moderate yields (d11-d16). Unexpectedly, chloro on para-position of phenyl rings has distinct corruption on the stereoselectivity, generating the product in 66% ee (d10). We think this could be ascribed to the weaker directing ability of the electron-deficient diphenylphosphine oxide group.
Furthermore, the scope of diaryliodonium salts for asymmetric C-3 arylation of diphenylphosphine oxide indole c1 was examined under the same conditions (Fig. 5). Groups with different electronic effects, like bromo, chloro, fluoro, methyl, ethoxycarbonyl, methoxy, and tert-butyl, were well tolerated and gave corresponding arylated products in 70-87% ee with moderate to good yields. As a whole, metaposition of substitutes on the phenyl ring of diaryliodonium salts renders low enantioselectivity than para-position, which is contrary to the tendency observed with phosphonic diamide a1 in Fig. 3. We speculated that the steric effect plays a more important role than the electronic effect during the construction of axial chirality, opposite to P-central chirality.

Synthetic applications
To further demonstrate the robustness of the developed method, the two arylation reactions were performed at the gram scale under adjusted conditions. With catalyst loading reduced to 1 mol%, orthoarylated product b6 was isolated in 83% yield with 91% ee after 72 h of heating (Fig. 6a). C-3 arylation product of c1 was obtained in 62% yield and 84% ee with 5 mol% catalyst loading (Fig. 6b). Meanwhile, slurry d1 in ethyl acetate (EA) could afford the enantio-enriched product in 96% ee, which offers further possibilities for application of this axially chiral biaryl monophosphine oxides in catalysis.

Mechanistic studies
As mentioned above, the electronic properties of the substrates had a substantial impact on the reactivities. To understand this reaction in more depth, unsymmetric phosphonic diamide a9 was synthesized and subjected to standard conditions (Fig. 7a). As expected, arylation predominantly occurred on the meta-methyl-substituted phenyl ring, and b29 was isolated in 61% yield, while arylated product b30 with an unsubstituted phenyl ring was observed as a minor product. This differentiating behavior of the reaction system implies that the catalyst selectively interacts with the phenyl ring in an electrophilic activated manner. Additionally, this reaction represents a successful example of distinguishing between two similar phenyl rings with subtle differences in the electronic density, which is hard to achieve by other asymmetric catalytic systems.
The kinetic isotope effect (KIE) was evaluated under standard conditions, and a value of 1.0 indicated that C-H bond abscission is not the rate-determining step in this reaction (Fig. 7b) 63 . Based on the observed results and literature reports 47,48 , we assumed that aryl-Cu(III) intermediate II was involved in the transformation, and this highly electrophilic complex, in a stereoselective and rate-limiting manner, activates an electron-rich phenyl ring with the aid of NaOTf to abstract H atoms and generate ortho-metalized intermediate IV, as depicted in Fig. 8. The whole C-H bond activation event determined the configuration of the product; however, more meticulous investigations are needed to elucidate the exact process of C-H bond activation and the origin of stereocontrol.
In summary, we have disclosed the Cu-catalyzed asymmetric arylation for the construction of P-chiral phosphonic diamines and axially chiral diarylphosphine oxide indoles with excellent enantioselectivities. Adequate but minimal NaOTf was found to be important   for achieving the high conversion of substrates. Electronic effects are fairly obvious in this reaction, and an electrophilic aryl-Cu(III) intermediate was thereby assumed. The KIE experiment shows that C-H bond abscission is not the rate-determining step in this Cu-catalyzed arylation process. The gram-scale reaction proceeded smoothly when the catalyst loading was reduced to 1 mol%, implying potential industrial applications. Further investigations to fully understand the reaction and extension of this methodology to construct other optically active structures are underway in our lab.

Data availability
The data that support the findings of this study are available within the paper and its Supplementary Information files. Crystallographic parameters for compounds b18 and d1 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2099084 and 2189868 (www.ccdc.cam.ac.uk/data_request/cif). All data are also available from authors upon request.  Article https://doi.org/10.1038/s41467-023-37987-8